Iron response element

Iron Response Element

The Iron Response Element (IRE) is a specific RNA sequence that plays a crucial role in the post-transcriptional regulation of genes involved in iron metabolism. IREs are found in the untranslated regions (UTRs) of mRNAs that encode proteins essential for iron homeostasis, such as ferritin and transferrin receptor. The regulation of these mRNAs by IREs is mediated by the Iron Regulatory Proteins (IRPs), which bind to the IREs in response to cellular iron levels.

Structure

The IRE is a conserved stem-loop structure located in the 5' or 3' UTRs of target mRNAs. The stem consists of a double-stranded RNA helix, while the loop contains a conserved sequence of nucleotides. The canonical IRE sequence includes a CAGUGN loop, where "N" represents any nucleotide, and a bulge in the stem that is critical for IRP binding.

Function

IREs function as regulatory elements that control the stability and translation of mRNAs in response to iron availability. When cellular iron levels are low, IRPs bind to IREs, leading to different regulatory outcomes depending on the location of the IRE:

• 5' UTR IREs: Found in mRNAs such as those encoding ferritin, IRP binding inhibits translation. This prevents the synthesis of ferritin, a protein that stores iron, thereby conserving iron for essential cellular processes.

• 3' UTR IREs: Found in mRNAs such as those encoding the transferrin receptor, IRP binding stabilizes the mRNA, increasing its half-life and allowing for more protein synthesis. This enhances the uptake of iron by increasing the number of transferrin receptors on the cell surface.

Iron Regulatory Proteins

The interaction between IREs and IRPs is central to the regulation of iron metabolism. There are two main IRPs, IRP1 and IRP2, which have distinct but overlapping roles:

• IRP1: Functions as an aconitase enzyme when iron is abundant, but switches to an RNA-binding protein under iron-deficient conditions.

• IRP2: Lacks aconitase activity and is primarily regulated by iron-dependent degradation.

Both IRPs bind to IREs with high affinity when iron levels are low, modulating the expression of target genes to maintain iron homeostasis.

Clinical Significance

Dysregulation of IRE-IRP interactions can lead to disorders of iron metabolism. For example, mutations in the IRE of the ferritin mRNA can cause hereditary hyperferritinemia-cataract syndrome, a condition characterized by elevated serum ferritin levels and early-onset cataracts. Additionally, aberrant IRP activity is implicated in diseases such as anemia of chronic disease and neurodegenerative disorders.

Research and Applications

Understanding the IRE-IRP regulatory system has implications for developing therapeutic strategies for iron-related disorders. Research is ongoing to explore small molecules that can modulate IRP activity or mimic IREs to correct dysregulated iron metabolism.

See Also

• Ferritin
• Transferrin receptor
• Iron metabolism
• RNA structure

References

• Hentze, M. W., & Kühn, L. C. (1996). Molecular control of vertebrate iron metabolism: mRNA-based regulatory circuits operated by iron, nitric oxide, and oxidative stress. *Proceedings of the National Academy of Sciences*, 93(16), 8175-8182.
• Rouault, T. A. (2006). The role of iron regulatory proteins in mammalian iron homeostasis and disease. *Nature Chemical Biology*, 2(8), 406-414.